Tracking Resistance to Artemisinin (TRAC)

NCT ID: NCT01350856

Last Updated: 2015-06-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1700 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-05-31
• Study Completion Date: 2014-12-31

Brief Summary

Because the artemisinins are the most potent antimalarial drugs, the reduction in parasite numbers is rapid. Therefore, early measures of reducing parasite counts are needed. This study will look at conventional markers of parasite reduction e.g. parasite clearance time, parasite reduction ratio, and the time to achieve a fall of 50%, 90% and 99% of the pre-treatment parasitaemia.

Defining artemisinin resistance requires the use of artesunate (AS) alone because it is now appreciated that the partner drug in a combination treatment has a significant impact on the rate of parasite clearance. This study will dose patients for 3 days with AS alone (or longer until parasites clear) and measure the parasite count frequently in order to be able to define an accurate regression line of a graph of the natural logarithm of the parasite count (Y axis) versus time (X axis). This will be followed by a full course of an artemisinin combination therapy (ACT). Two different dose regimens of artesunate will be compared at all sites except those in western Cambodia, as unpublished observations from the Thai-Myanmar border suggest the standard lower daily dose of 2mg/kg may enable the earlier detection of low level resistance than a 4mg/kg daily dose.

Detailed Description

Background:

Artemisinins are the cornerstone of current antimalarial treatment. Evidence of reduced susceptibility to artemisinins in Western Cambodia was first presented in January 2007 and confirmed in a subsequent detailed pharmacokinetic-pharmacodynamic study conducted by our group. Artemisinin resistance was manifest by a marked slowing of parasite clearance. The spread of highly artemisinin resistant falciparum malaria would have devastating consequences for malaria control and elimination. The response to artemisinin resistance in P. falciparum depends critically upon answering one pivotal question: how far has it spread? This research proposal focuses on filling critical gaps in knowledge that are essential to planning an effective response.

Objectives/Hypothesis/Questions:

This is a multi-centre study with the primary objective of comparing the P. falciparum parasite clearance compared to a reference parasite clearance rate obtained from historical data in artemisinin sensitive falciparum malaria.

The aim of this large scale study is to determine if artemisinin resistance has spread and if so, how far it has spread.

Research design:

This is a multi-centre, open-label randomised trial to assess the clearance rates of peripheral blood P. falciparum parasitaemias in patients with acute uncomplicated falciparum malaria treated with two different doses of artesunate.

The study will recruit patients with acute uncomplicated P. falciparum malaria. The total number of patients for this study is expected to be 1800.

Patients will be randomised 1:1 to receive either:

• AS2: Artesunate 2 mg/kg/day for 3 days OR
• AS4: Artesunate 4 mg/kg/day for 3 days
• followed by a full course of Artesunate- mefloquine (MAS3) Patients will be hospitalised for at least the 1st three days. During hospitalisation, patients will have malaria parasite count done at 0, 4, 6, 8, 12, then every 6 hours until parasite clearance. The weekly follow up is until day 14 (on Day 7 and Day 14).

Value and significance of the research The study aims to address a simple but crucial question regarding artemisinin resistance for which currently there is no answer: has artemisinin resistant Plasmodium falciparum spread from Western Cambodia? The results will determine how to approach the subsequent efforts; strengthening of strategies for eliminating the resistant parasites in Western Cambodia if the resistance is confined to this area, or for containment and malaria control if the resistant parasites have already spread.

Potential outcomes Within one year we expect to produce a map of the geographical extent, prevalence and severity of artemisinin resistance.

Conditions

Falciparum Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Artesunate 2

Artesunate 2 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine

Group Type: ACTIVE_COMPARATOR

Artesunate 2

Intervention Type: DRUG

Artesunate 2 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine

Artesunate 4

Artesunate 4 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine

Group Type: EXPERIMENTAL

Artesunate 4

Intervention Type: DRUG

Artesunate 4 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine

Interventions

Artesunate 2

Artesunate 2 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine

Intervention Type: DRUG

Artesunate 4

Artesunate 4 mg/kg/day for 3 days followed by a full course of either artemether-lumefantrine or DHA-piperaquine or artesunate-mefloquine or artesunate-amodiaquine

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female, aged from 6 months to 65 years old, inclusive
• Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species)
• Asexual P. falciparum parasitaemia: 10,000 to 200,000/uL, determined on a thin or thick blood film
• Fever defined as > 37.5°C tympanic temperature or a history of fever within the last 24 hours
• Written informed consent (by legally acceptable representative in case of children)
• Willingness and ability of the patients/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria

• Signs of severe/complicated malaria (WHO, 2000)
• Haematocrit < 25% or haemoglobin (Hb) < 8 g/dL at enrollment
• Acute illness other than malaria requiring treatment
• For females: pregnancy, breast feeding
• Patients who have received artemisinin or a derivative or an artemisinin-containing combination therapy (ACT) within the previous 7 days
• History of allergy or known contraindication to artemisinins, or to the ACT to be used at the site
• Previous splenectomy

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mahidol University

OTHER

Sponsor Role: collaborator

Worldwide Antimalarial Resistance Network

NETWORK

Sponsor Role: collaborator

University of Oxford

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicholas J White, DSc MD

Role: PRINCIPAL_INVESTIGATOR

Mahidol Oxford Tropical Medicine Research Unit

Locations

Ramu Upazila Health Complex

Cox's Bazaar, , Bangladesh

Myitkyina

Myitkyina, Kachin State, Burma

Day Bu Noh

Luthaw, Kayin State, Burma

Pyin Oo Lwin

Mandalay, Mandalay Region, Burma

Thabeikkyin Hospital

Thabeikkyin, Mandalay Region, Burma

Shwe Kyin Hospital

Shwe Kyin, , Burma

Pursat Referral Hospital

Pursat, Pursat, Cambodia

Pailin General Hospital

Pailin, , Cambodia

District Referral Hospital

Preah Vihear, , Cambodia

District Referral Hospital

Rattanakiri, , Cambodia

Kingasani Health Centre

Kinshasa, , Democratic Republic of the Congo

Sulkapara Block Primary Health Center

West Bengal, West Bengal, India

Pingilikani Dispensary

Kilifi, , Kenya

Phouvong District Hospital

Phouvong, Attapeu, Laos

University of Ilorin Teaching Hospital

Ilorin, , Nigeria

Shoklo Malaria Research Unit

Mae Sot, Changwat Tak, Thailand

Kraburi Hospital

Ranong, , Thailand

Phusing Hospital

Si Sa Ket, , Thailand

Phuoc Long Hospital

Bình Phước, Binh Phuoc, Vietnam

Countries

Bangladesh; Burma; Cambodia; Democratic Republic of the Congo; India; Kenya; Laos; Nigeria; Thailand; Vietnam

References

Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM, Mao S, Sam B, Sopha C, Chuor CM, Nguon C, Sovannaroth S, Pukrittayakamee S, Jittamala P, Chotivanich K, Chutasmit K, Suchatsoonthorn C, Runcharoen R, Hien TT, Thuy-Nhien NT, Thanh NV, Phu NH, Htut Y, Han KT, Aye KH, Mokuolu OA, Olaosebikan RR, Folaranmi OO, Mayxay M, Khanthavong M, Hongvanthong B, Newton PN, Onyamboko MA, Fanello CI, Tshefu AK, Mishra N, Valecha N, Phyo AP, Nosten F, Yi P, Tripura R, Borrmann S, Bashraheil M, Peshu J, Faiz MA, Ghose A, Hossain MA, Samad R, Rahman MR, Hasan MM, Islam A, Miotto O, Amato R, MacInnis B, Stalker J, Kwiatkowski DP, Bozdech Z, Jeeyapant A, Cheah PY, Sakulthaew T, Chalk J, Intharabut B, Silamut K, Lee SJ, Vihokhern B, Kunasol C, Imwong M, Tarning J, Taylor WJ, Yeung S, Woodrow CJ, Flegg JA, Das D, Smith J, Venkatesan M, Plowe CV, Stepniewska K, Guerin PJ, Dondorp AM, Day NP, White NJ; Tracking Resistance to Artemisinin Collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014 Jul 31;371(5):411-23. doi: 10.1056/NEJMoa1314981.

Reference Type: DERIVED

PMID: 25075834 (View on PubMed)

Other Identifiers

BAKMAL1101

Identifier Type: -

Identifier Source: org_study_id